A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers

Carter, Scott L.; Eklund, Aron C.; Kohane, Isaac S.; Harris, Lyndsay N.; Szállási, Zoltán

doi:10.1038/ng1861

Cited by 1,047 publications

(1,149 citation statements)

References 26 publications

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“…UW473 cells were relatively more sensitive to CDDP, MTX, and TMZ treatments and more resistant to DX than UW402 cell line. Although it has been largely described that CIN confers intrinsic multidrug resistance in tumors (Sheltzer and Amon 2011;Lee et al 2011) and consequently poorer prognosis in cancer patients (Carter et al 2006), in our study, UW473 showed a greater CIN phenotype and it was more chemosensitivity than UW402, which could confirm the hypothesis that excessive genomic instability may surpass a threshold compatible with cell viability (Cahill et al 1999). This concept has been recently corroborated in the clinical context through studies reporting a paradoxical relationship between CIN and survival outcome in cancer, being that tumors exhibiting extreme CIN displayed improved prognosis relative to tumors with intermediate levels of CIN Roylance et al 2011;McGranahan et al 2012;Lee and Swanton 2012).…”

Section: Discussionsupporting

confidence: 77%

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

et al. 2013

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Chromosomal heterogeneity is a hallmark of most tumors and it can drive critical events as growth advantages, survival advantages, progression and karyotypic evolution. Medulloblastoma (MB) is the most common malignant central nervous system tumor in children. This work attempted to investigate chromosomal heterogeneity and instability profiles of two MB pediatric cell lines and their relationship with cell phenotype. We performed GTG-banding and cytokinesis-block micronucleus cytome assays, as well as morphological characterization, cell population doubling time, colony-forming efficiency, and chemo-sensitivity assays in two pediatric MB cell lines (UW402 and UW473). Both MB cells showed a high chromosomal heterogeneity. UW473 cells showed *2 fold higher both clonal-and non-clonal chromosomal alterations than UW402 cells. Besides, UW473 showed two clonal-groups well-differentiated by ploidy level (\2n[and\4n[) and also presented a significantly higher number of chromosomal instability biomarkers. These results were associated with high morphological heterogeneity and survival advantages for UW473 and proliferation advantages for UW402 cells. Moreover, UW473 was significantly more sensitive to methotrexate, temozolomide and cisplatin while UW402 cells were more sensitive to doxorubicin. These data suggest that distinct different degrees of karyotypic heterogeneity and instability may affect neoplasic phenotype of MB cells. These findings bring new insights into cell and tumor biology.

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Section: Discussionsupporting

confidence: 77%

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

et al. 2013

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“…33,34 Notably, the amplifications of loci containing MDM2 and CDK4 did not significantly correlate with the chromosome instability index, suggesting that these changes might not be randomly secondary to global chromosomal instability. Together with its frequent occurrence, this finding indicated critical roles for MDM2 and CDK4 amplification in the tumorigenesis of a subset of adenosarcomas.…”

Section: Discussionmentioning

confidence: 94%

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Lee

Changou

et al. 2016

Modern Pathology

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Müllerian adenosarcomas are malignant gynecologic neoplasms. Advanced staging and sarcomatous overgrowth predict poor prognosis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Copy number variations, particularly losses, were significantly higher in cases with sarcomatous overgrowth. Frequent gains of chromosomal 12q were noted, often involving cancer-associated genes CDK4 (six cases), MDM2, CPM, YEATS4, DDIT3, GLI1 (five each), HMGA2 and STAT6 (four), without association with sarcomatous overgrowth status. The most frequent losses involved chromosomes 13q (five cases), 9p, 16q and 17q (four cases each) and were almost limited to cases with sarcomatous overgrowth. MDM2 and CDK4 amplification, as well as losses of RB1 (observed in two cases) and CDKN2A/B (one case), was verified by FISH. By immunohistochemistry, all MDM2/CDK4-coamplified cases were confirmed to overexpress both encoded proteins, whereas all four cases with (plus an additional four without) gain of HMGA2 overexpressed the HMGA2 protein. Both cases with RB1 loss were negative for the immunostaining of the encoded protein. Chromothripsis-like copy number profiles involving chromosome 12 or 14 were observed in three fatal cases, all of which harbored sarcomatous overgrowth. With whole chromosome painting and deconvolution fluorescent microscopy, dividing tumor cells in all three cases were shown to have scattered extrachromosomal materials derived from chromosomes involved by chromothripsis, suggesting that this phenomenon may serve as visual evidence for chromothripsis in paraffin

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“…[2] Furthermore, aneuploidy is associated with poor patient survival. [80][81][82][83][84][85][86][87][88][89] The karyotypes observed in cancer are not random, as different cancer types display specific karyotypes. [36,72,90] While certain forms of aneuploidy can be beneficial to tumor growth, the relationship between cancer and CIN remains paradoxical.…”

Section: Cin Can Have Highly Differential Effects On Cellsmentioning

confidence: 99%

CIN and Aneuploidy: Different Concepts, Different Consequences

Schukken

Foijer

2017

BioEssays

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Chromosomal instability (CIN) and aneuploidy are similar concepts but not synonymous. CIN is the process that leads to chromosome copy number alterations, and aneuploidy is the result. While CIN and resulting aneuploidy often cause growth defects, they are also selected for in cancer cells. Although such contradicting fates may seem paradoxical at first, they can be better understood when CIN and aneuploidy are assessed separately, taking into account the in vitro or in vivo context, the rate of CIN, and severity of the aneuploid karyotype. As CIN can only be measured in living cells, which proves to be technically challenging in vivo, aneuploidy is more frequently quantified. However, CIN rates might be more predictive for tumor outcome than assessing aneuploidy rates alone. In reviewing the literature, we therefore conclude that there is an urgent need for new models in which we can monitor chromosome mis-segregation and its consequences in vivo. Also see the video abstract here: https://youtu.be/fL3LxZduchg

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A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers

Cited by 1,047 publications

References 26 publications

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

CIN and Aneuploidy: Different Concepts, Different Consequences

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